Activated Protein C for Treatment of Radiation Combined Injury

描述（由申请人提供）：本申请响应RFA-AI-07-038，寻求支持评估重组活化蛋白C （APC）在治疗辐射损伤合并炎症和感染中的应用。在动物模型和人类患者中，APC已被证明可以降低败血症死亡率，并被批准用于治疗严重败血症的临床应用。我们的初步数据支持APC在体内保护造血干细胞免受辐射，从而降低全身照射后的死亡率的观点，可能是通过对多器官系统的不同机制作用，包括：对血管内皮的促生存和抗炎作用以及对造血祖细胞的细胞保护/增殖作用。APC疗法已经被FDA批准用于治疗严重败血症，这些特性使得APC疗法成为治疗联合放射损伤的理想选择。该申请的R21阶段将(1)在小鼠模型中提供原理证明，在致死性全身辐射暴露后，除了致死性全身辐射暴露并随后感染引起的致死性外，APC作为单丸输注可以防止骨髓衰竭造成的致死性；(2)建立一种给药方案，以优化总体疗效，并扩大在辐射暴露后给予APC并仍能预防死亡的时间窗口。该研究的R33期将(1)探索利用具有选择性修饰生物活性的重组APC变体是否可以进一步提高APC治疗的疗效和安全性；(2)为人APC对移植到人类异种移植物允许的NOG小鼠体内的人造血细胞的放射防护效果提供证据；(3)为暴露后APC治疗预防胃肠道损伤死亡的潜在疗效提供证据。拟议研究的结果将为进一步探索APC的临床应用以及可能更安全、疗效更高的重组APC变体作为致命辐射暴露后的救命治疗提供强有力的激励。除了将APC作为一种安全有效的抗辐射复合损伤的对策外，这些研究的见解将为研究天然蛋白C抗凝途径与造血系统抗辐射损伤保护之间的全新联系的细胞和分子基础奠定坚实的基础。本申请评估了内源性活化蛋白C （APC）分子重组形式在治疗性预防骨髓衰竭、感染和最终死亡方面的应用，因为它们可能在偶然的全身暴露于核辐射后发生。该研究的结果有望验证APC作为一种安全有效的治疗核事故和其他涉及辐射暴露威胁的受害者的方法。

DESCRIPTION (provided by applicant): This application responds to RFA-AI-07-038 and seeks support for evaluating the use of the recombinant activated protein C (APC) in the treatment of radiation injury combined with inflammation and infection. APC has been already shown to reduce sepsis mortality in animal models and in human patients, and is approved for clinical use in the treatment of severe sepsis. Our preliminary data support the notion that APC protects hematopoietic stem cells from irradiation in vivo and thereby reduces mortality after whole body irradiation, possibly via mechanistically diverse effects on multiple organ systems, including: survival-promoting and anti-inflammatory effects on vascular endothelium and cytoprotective/proliferative effects on hematopoietic progenitors. These properties make APC therapy, which is already FDA approved for severe sepsis, an ideal candidate for the treatment of combined radiation injury. The R21 phase of this application will (1) provide proof-of-principle in a mouse model that APC administered as a single bolus infusion after lethal whole body radiation exposure can prevent lethality from bone marrow failure, in addition to lethality caused by lethal whole body radiation exposure compounded by subsequent infection; and (2) establish a dosing regimen to optimize overall efficacy and to expand the time window after which APC can be given following radiation exposure and still prevent mortality. The R33 phase of the study will (1) explore whether efficacy and safety of APC therapy can be further improved by the use of recombinant APC variants with selectively modified bioactivities, (2) generate evidence for the in vivo efficacy of human APC in the radioprotection of human hematopoietic cells transplanted into human xenograft-permissive NOG mice; and (3) generate evidence for the potential efficacy of post-exposure APC therapy in preventing death caused by gastrointestinal injury. Outcomes of the proposed studies will provide a strong incentive to further explore the clinical use of APC, and possibly safer recombinant APC variants with improved efficacy, as a life-saving treatment after lethal radiation exposure. In addition to developing APC as a safe and effective countermeasure against radiation combined injury, insights expected from these studies will lay a solid foundation for investigating the cellular and molecular basis of this entirely novel connection between the natural protein C anticoagulant pathway and protection of the hematopoietic system against radiation injury. This application evaluates the use of recombinant forms of the endogenous activated protein C (APC) molecule for the therapeutic prevention of bone marrow failure, infection, and ultimately mortality as they may occur after incidental whole body exposure to nuclear radiation. Outcomes of the study are expected to validate APC as a safe and effective treatment for victims of nuclear accidents and other threats involving radiation exposure.